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Project description:Williams-Beuren syndrome (WBS) is a relatively rare disease caused by the deletion of 1.5 to 1.8 Mb on chromosome 7 which contains approximately 28 genes. This multisystem disorder is mainly characterized by supravalvular aortic stenosis, mental retardation, and distinctive facial features. We generated mouse embryonic stem (ES) cells clones expressing each of the 4 human WBS genes (WBSCR1, GTF2I, GTF2IRD1 and GTF2IRD2) found in the specific delated region 7q11.23 causative of the WBS. We generated at least three stable clones for each gene with stable integration in the ROSA26 locus of a tetracycline-inducible upstream of the coding sequence of the genet tagged with a 3xFLAG epitope. Three clones for each gene were transcriptionally profiled in inducing versus non-inducing conditions for a total of 24 profiles. This small collection of human WBS-ES cell clones represents a resource to facilitate the study of the function of these genes during differentiation.
| S-EPMC6834640 | biostudies-literature
Project description:A transcriptomic study of Williams-Beuren syndrome associated genes in mouse embryonic stem
| PRJNA379421 | ENA
Project description:BACKGROUND: Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder. METHODOLOGY: The study was conducted on 9 French individuals aged from 4 to 37 years old with autistic disorder associated with WBS. Behavioral assessments were performed using Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) scales. Molecular characterization of the WBS critical region was performed by FISH. FINDINGS: FISH analysis indicated that all 9 patients displayed the common WBS deletion. All 9 patients met ADI-R and ADOS diagnostic criteria for autism, displaying stereotypies and severe impairments in social interaction and communication (including the absence of expressive language). Additionally, patients showed improvement in social communication over time. CONCLUSIONS: The results indicate that comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism.
| S-EPMC3295800 | biostudies-other
Project description:Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value?<?0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses.
| S-EPMC6007881 | biostudies-literature
Project description:Williams-Beuren syndrome (WBS; OMIM #194050) is a developmental disorder characterized by congenital heart disease, intellectual disability, dysmorphic facial features and ophthalmologic abnormalities. Oral abnormalities are also described in clinical manifestations of the disease. This paper describes orofacial features in patients with WBS.Seventeen patients with a confirmed molecular diagnosis of WBS were examined for oral abnormalities through clinical oral evaluations and panoramic radiography.Malocclusion, specifically with dental midline deviation, and high-arched palate were the most common findings.The present results contribute to knowledge on the orofacial manifestations of WBS. Since such patients with WBS may develop severe oral abnormalities, early detection and treatment can help improve their quality of life.
| S-EPMC5822531 | biostudies-literature
Project description:Williams-Beuren syndrome (WBS) is a segmental aneusomy syndrome that results from a heterozygous deletion of contiguous genes at 7q11.23. Three large region-specific low-copy repeat elements (LCRs), composed of different blocks (A, B, and C), flank the WBS deletion interval and are thought to predispose to misalignment and unequal crossing-over, causing the deletions. In this study, we have determined the exact deletion size and LCR copy number in 74 patients with WBS, as well as precisely defined deletion breakpoints in 30 of them, using LCR-specific nucleotide differences. Most patients (95%) exhibit a 1.55-Mb deletion caused by recombination between centromeric and medial block B copies, which share approximately 99.6% sequence identity along 105-143 kb. In these cases, deletion breakpoints were mapped at several sites within the recombinant block B, with a cluster (>27%) occurring at a 12 kb region within the GTF2I/GTF2IP1 gene. Almost one-third (28%) of the transmitting progenitors were found to be heterozygous for an inversion between centromeric and telomeric LCRs. All deletion breakpoints in the patients with the inversion occurred in the distal 38-kb block B region only present in the telomeric and medial copies. Finally, only four patients (5%) displayed a larger deletion ( approximately 1.84 Mb) caused by recombination between centromeric and medial block A copies. We propose models for the specific pairing and precise aberrant recombination leading to each of the different germline rearrangements that occur in this region, including inversions and deletions associated with WBS. Chromosomal instability at 7q11.23 is directly related to the genomic structure of the region.
| S-EPMC1180575 | biostudies-literature
Project description:OBJECTIVE:To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study. STUDY DESIGN:Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities. RESULTS:On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported. CONCLUSIONS:Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.
| S-EPMC5085847 | biostudies-literature
Project description:Although considerable progress has been made in understanding the genetic basis of morphologic traits (for example, body size and coat color) in dogs and wolves, the genetic basis of their behavioral divergence is poorly understood. An integrative approach using both behavioral and genetic data is required to understand the molecular underpinnings of the various behavioral characteristics associated with domestication. We analyze a 5-Mb genomic region on chromosome 6 previously found to be under positive selection in domestic dog breeds. Deletion of this region in humans is linked to Williams-Beuren syndrome (WBS), a multisystem congenital disorder characterized by hypersocial behavior. We associate quantitative data on behavioral phenotypes symptomatic of WBS in humans with structural changes in the WBS locus in dogs. We find that hypersociability, a central feature of WBS, is also a core element of domestication that distinguishes dogs from wolves. We provide evidence that structural variants in GTF2I and GTF2IRD1, genes previously implicated in the behavioral phenotype of patients with WBS and contained within the WBS locus, contribute to extreme sociability in dogs. This finding suggests that there are commonalities in the genetic architecture of WBS and canine tameness and that directional selection may have targeted a unique set of linked behavioral genes of large phenotypic effect, allowing for rapid behavioral divergence of dogs and wolves, facilitating coexistence with humans.
| S-EPMC5517105 | biostudies-literature
Project description:AimsThe Williams-Beuren syndrome (WBS) is a genetic disorder caused by a heterozygous ~1.5-Mb deletion. The aim of this study was to determine how the genetic changes in a Wbs mouse model alter Eln expression, blood pressure, vessel structure, and abdominal aortic wall dynamics in vivo.MethodsElastin (ELN) transcript levels were quantified by qRT-PCR and blood pressure was measured with a tail cuff system. M-mode ultrasound was used to track pulsatile abdominal aortic wall motion. Aortas were sectioned and stained to determine medial lamellar structure.ResultsELN transcript levels were reduced by 38-41% in Wbs mice lacking one copy of the ELN gene. These mice also had a 10-20% increase in mean blood pressure and significantly reduced circumferential cyclic strain (p < 0.001). Finally, histological sections showed disorganized and fragmented elastin sheets in Wbs mice, but not the characteristic increase in lamellar units seen in Eln(+/-) mice.ConclusionsThe deletion of Eln in this Wbs mouse model results in lower gene expression, hypertension, reduced cyclic strain, and fragmented elastin sheets. The observation that the number of medial lamellar units is normal in Wbs deletion mice, which is in contrast to Eln(+/-) mice, suggests other genes may be involved in vascular development.
| S-EPMC2975735 | biostudies-literature
Project description:Williams-Beuren syndrome (WBS, no. OMIM 194050) is a rare multisystem genetic disorder caused by a microdeletion on chromosome 7q11.23 and characterized by cardiovascular malformations, mental retardation, and a specific facial dysmorphism. Recently, we reported that a series of non?Hodgkin's lymphoma occurs in children with WBS and thus hypothesized that a predisposition to cancer may be associated with this genetic disorder. The aim of the present study was to ascertain the role played by three genes hemizygously deleted in WBS (RFC2, GTF2I and BAZ1B) in DNA damage response pathways. Cell proliferation, cell cycle analysis, ??H2A.X induction, and expression of DNA damage response proteins were investigated upon exposure to genotoxic treatments in WBS patient?derived primary fibroblasts and in the 293T cell line treated with specific siRNAs targeting RFC2, GTF2I and BAZ1B. An impaired hydroxyurea?induced phosphorylation of CHK1 was observed in the WBS cells. However, this defective DNA damage response was not associated with an increased sensitivity to genotoxic agents. In addition, depletion of RFC2, GTF2I and BAZ1B using specific siRNAs did not have a significant impact on the DNA damage response in 293T cells. Our results highlight that the ATR?dependent DNA damage response is impaired in WBS patient cells but is also dispensable for viability when these cells undergo a genotoxic stress. The mechanism by which the ATR pathway is impaired in WBS warrants elucidation through further investigation.
| S-EPMC5360356 | biostudies-literature